Project Summary/Abstract Concurrent nicotine use is highly implicated in the propensity to misuse prescribed opiates, future development of opiate dependence, and susceptibility to accidental opiate overdose. Approximately 83-95% of patients involved in opioid treatment programs are tobacco users. As such, there exists a clear public health mandate for elucidation of mechanisms contributing to opiate addiction liability resultant from opiate and nicotine polysubstance use. The anterior insular cortex is heavily involved in processing the interoceptive stimulus properties of commonly abused drugs and insular dysfunction is implicated in the development and maintenance of substance use disorders. The role of the insular cortex in opiate addiction, and furthermore, how nicotine may play a role, is currently underexplored. There is emerging evidence that nicotine interferes with insular function, specifically through depressing synaptic potentiation and inhibiting the output of the insular cortex. Preliminary data demonstrate that nicotine delivered to the anterior insular cortex interferes with the processing of the stimulus properties of opiates in a quantitative manner, an effect remarkably similar to insular chemogenetic inactivation. Specifically, subjects either administered nicotine or undergoing chemogenetic inactivation of the insular cortex behave as if they have received a lower dose of morphine relative to controls in paradigms examining both the reinforcing (conditioned place preference; CPP) and aversive (conditioned taste avoidance; CTA) stimulus properties of opiates. As a result, tobacco smokers may require more and stronger doses of opiates in order to achieve the desired effects. This reduced sensitivity to the stimulus properties of opiates due to nicotine co-use may facilitate the development of opiate dependence. The goal of this project is to elucidate the mechanisms and neural circuits through which insular cortical nicotinic activity contributes to enhanced opiate addiction liability. These experiments will employ a combination of psychophysical behavioral measures, site-specific behavioral pharmacology, circuit-specific chemogenetic manipulation, and in vivo electrophysiology in order to fully characterize the mechanisms through which insular cortical nicotinic activity may contribute to the development of opiate substance use disorders. Furthermore, through completion of these proposed studies, the applicant will be competently trained in new technical skills and perspectives, ultimately facilitating a successful transition to a principal investigator conducting programmatic research on the comorbidity of nicotine and opiate abuse.